Rheumatoid arthritis (RA) is an immune-mediated, systemic inflammatory disease that affects mainly synovial joins, with intra-articular inflammation, synovial hyperplasia and progressive degradation of cartilage and bone. Prevalence of the disease is about 1% of the population, and the disease is more frequent (and perhaps worse) in women than in men. There have been clear advances in the pharmacological management of rheumatoid arthritis over the last decade, but many patients still do not tolerate or do not respond well to the available therapies.
Moreover, the control and management of arthritis associated pain and inflammation in animals, such as companion animals, specifically in dogs, is also an area of growing interest. Many FDA-approved drugs are available to treat pain associated with osteoarthritis (OA) in dogs (e.g., carprofen, firocoxib, meloxicam, deracoxib, and robenacoxib), all of which work by inhibiting cyclooxygenase enzymes. The FDA approved COX inhibitor NSAIDs for use in dogs, unless contra-indicated, are consider to be effective treatments for the pain associated with RA. These COX-inhibiting NSAIDs, as a class, however, carry the potential for adverse effects including gastrointestinal ulceration and perforation, and renal insufficiency. The Food and Drug Administration (FDA) has required language in the precaution section of the package inserts of these drugs warning that, as a class, they may be associated with renal, gastrointestinal (GI), and hepatic toxicity. Specifically, labels of these drugs warn of the “potential to produce GI ulceration and/or GI perforation”.
Prostaglandins are mediators of pain, fever and other symptoms associated with inflammation. Especially prostaglandin E2 (PGE2) is the predominant eicosanoid detected in inflammation conditions. In addition, it is also involved in various physiological and/or pathological conditions and such as hyperalgesia, uterine contraction, digestive peristalsis, awakeness, suppression of gastric acid secretion, blood pressure, platelet function, bone metabolism, angiogenesis or the like.
Four PGE2 receptor subtypes (EP1, EP2, EP3 and EP4) displaying different pharmacological properties have been cloned. EP4 subtype, a Gs-coupled receptor stimulates cAMP production, and is distributed in a wide variety of tissue suggesting a major role in PGE2-mediated biological events.
Among the multiple targets involved in the pathogenesis of rheumatoid arthritis, the prostaglandin E2 receptor 4 (EP4) subtype receptor of prostaglandin E2 (PGE2) is one of the most promising because, unlike common NSAIDs that inhibit the synthesis of prostaglandins, selective EP4 antagonists have the potential to combine immunomodulatory and direct anti-inflammatory properties. Furthermore, the EP4 receptor in mice, humans and dogs has been cloned and characterized and the canine EP4 receptor has approximately 90% homology to the human receptor. EP4 antagonists present an opportunity for a novel pharmaceutical or veterinary therapy.
Grapiprant, whose chemical name is N-[[[2-[4-(2-Ethyl-4,6-dimethyl-1H-imidazo[4,5-c] pyridin-1-yl)phenyl]ethyl]amino]carbonyl]-4 methylbenzenesulfonamide, and sold under the tradename Galliprant®, is a prostaglandin E2 (PGE2) EP4 receptor antagonist; a non-cyclooxygenase (COX) inhibiting, non-steroidal anti-inflammatory drug (NSAID) in the piprant class. Grapiprant is indicated for the control of pain and inflammation associated with osteoarthritis (OA) in dogs. Further reference is made to WO 2002/032422, WO 2002/032900, WO 2006/095268, as well as WO 2003/086371, WO 2011/102149, and WO 2014/148053. Additional background research regarding compounds with an imidazopyridine or imidazopyrazine core ring structure include US 2013/195848, WO 2014/078813, WO 2011/151259, WO 2011/113862, US 2005/0009832, US 2004/0220189, WO 2006/091671, and WO 2018/013430. All of these cited patent publications are incorporated by reference with regard to their background teaching.
Despite this background of research and development, there remains a need for novel EP4 antagonists to offer safe and effective pharmaceutical or veterinary therapy.